title: The ratio of arginine to dimethylarginines is reduced and predicts outcomes in patients with severe sepsis.
abstract: OBJECTIVE
  Arginine deficiency may contribute to microvascular dysfunction, but previous studies suggest that arginine supplementation may be harmful in sepsis. Systemic arginine availability can be estimated by measuring the ratio of arginine to its endogenous inhibitors, asymmetric and symmetric dimethylarginine. We hypothesized that the arginine-to-dimethylarginine ratio is reduced in patients with severe sepsis and associated with severity of illness and outcomes.
  
  
  METHODS
  Case-control and prospective cohort study.
  
  
  METHODS
  Medical and surgical intensive care units of an academic medical center.
  
  
  METHODS
  One hundred nine severe sepsis and 50 control subjects.
  
  
  RESULTS
  Plasma and urine were obtained in control subjects and within 48 hrs of diagnosis in severe sepsis patients. The arginine-to-dimethylarginine ratio was higher in control subjects vs. sepsis patients (median, 95; interquartile range, 85-114; vs. median, 34; interquartile range, 24-48; p < .001) and in hospital survivors vs. nonsurvivors (median, 39; interquartile range, 26-52; vs. median, 27; interquartile range, 19-32; p = .004). The arginine-to-dimethylarginine ratio was correlated with Acute Physiology and Chronic Health Evaluation II score (Spearman's correlation coefficient [ρ] = - 0.40; p < .001) and organ-failure free days (ρ = 0.30; p = .001). A declining arginine-to-dimethylarginine ratio was independently associated with hospital mortality (odds ratio, 1.63 per quartile; 95% confidence interval, 1.00-2.65; p = .048) and risk of death over the course of 6 months (hazard ratio, 1.41 per quartile; 95% confidence interval, 1.01-1.98; p = .043). The arginine-to-dimethylarginine ratio was correlated with the urinary nitrate-to-creatinine ratio (ρ = 0.46; p < .001).
  
  
  CONCLUSIONS
  The arginine-to-dimethylarginine ratio is associated with severe sepsis, severity of illness, and clinical outcomes. The arginine-to-dimethylarginine ratio may be a useful biomarker, and interventions designed to augment systemic arginine availability in severe sepsis may still be worthy of investigation.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Nursing, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gough
authors.forename: Mary Anne M
authors.initials: MA
authors.lastname: Morgan
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Mack
authors.forename: Denise C
authors.initials: DC
authors.lastname: Darling
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Frasier
authors.forename: Kathleen P
authors.initials: KP
authors.lastname: Doolin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Apostolakos
authors.forename: Judith C
authors.initials: JC
authors.lastname: Stewart
authors.forename: Brian T
authors.initials: BT
authors.lastname: Graves
authors.forename: Erland
authors.initials: E
authors.lastname: Arning
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mooney
authors.forename: Mark W
authors.initials: MW
authors.lastname: Frampton
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Pietropaoli
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D018805:Sepsis / Q000097:blood* / Q000401:mortality / Q000628:therapy; D012720:Severity of Illness Index; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; C487735:dimethylarginine; D001120:Arginine